Irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin) is a semisynthetic analogue of the natural alkaloid camptothecin extracted from plants such as Camptotheca acuminata. Irinotecan is an antineoplastic agent of the topoisomerase I inhibitor class and used in the treatment of various types of cancer like metastatic colorectal cancer (mCRC), non-small cell lung cancer (NSCLC) and triple negative breast cancer. Irinotecan is a precursor for and is in the body converted by carboxylesterase enzymes primarily in the liver to the active metabolite SN-38. SN-38 is approximately 100-1000 times more cytotoxic than irinotecan in human and rodent tumor cell lines. In vitro irinotecan displays cytotoxic activity in tumor cells with IC50 values for irinotecan in the range 1.6 to 24 mg/L while those of SN-38 are in the range 2 to 14 μg/L as given by Chabot R G [1]. Irinotecan and its active metabolite SN-38 bind to the topoisomerase I-DNA complex and prevent the DNA from unwinding. Since topoisomerase I complexes with DNA only during DNA synthesis, the cytotoxic action of the irinotecan metabolite likely takes place during S-phase. The formation of a topoisomerase I/camptothecin/DNA-cleavable complex results in cell injury or death.
Irinotecan is currently only administered as an aqueous solution for intravenous infusion over 30-90 minutes weekly or every 3rd week. The product is originally marketed as an infusion concentrate under the trade names CAMPTOSAR® or CAMPTO® and in the form of irinotecan, hydrochloride trihydrate (a salt of the irinotecan base).
A solid oral dosage form like a tablet formulation could provide significant convenience benefit to the patients, who today have to attend the clinics or hospitals at repetitive visits over longer period to receive their intravenous chemotherapy medication. Development of an oral product for home treatment will prevent the patient from being tied up to an infusor at the hospital a thus significantly improve the quality of life for patients who need to undergo multiple cycles of treatment. From a pharmaco-economic perspective, outpatient treatment will offer the society a significant reduction in health care costs to treat the individual patient, if the patient can take his medication at home.
In addition, the availability of an oral treatment will make alternative dosing schedules such as more frequent dosing with a smaller dose much more feasible. By more frequent dosing, the cancer cells will have prolonged exposure to the cell cycle specific action of irinotecan improving the anti-tumor activity. At a lower but more frequent dose, the side effects may be reduced while maintaining the same or better efficiency on tumor cells by targeting more cells in the active S-phase. A more frequent dosing regimen of irinotecan was shown to have a significant benefit both in terms of lower toxicity for the host and in efficacy in terms of time to progression and overall survival for patient treated with irinotecan [2; 3; 4]. Metronomic dosing or dose dense therapy, i.e. giving the chemotherapy at regular intervals at a low dose is a relative new concept within chemotherapy that was pioneered e.g. by Robet Kerble from the University of Toronto [5].
Several attempts have been made in order to prepare oral formulations of irinotecan as described by Kuppens et al [6]. All of these efforts have been based on the Irinotecan, hydrochloride, trihydrate salt. Initial human phase I oral studies were performed using the intravenous product. The product was orally administered together with juice for masking of the bitter taste and for prevention of nausea upon intake [7; 8; 9]. More easily used oral formulations included 5, 20 and 50 mg powder-filled capsules [10; 11; 12; 13]. Also 5, 20 and 50 mg semi-solid matrix capsules for extended release of irinotecan were attempted [14; 15; 16; 17]. Clinical phase I studies using these formulations show that oral administration of irinotecan is feasible and may have favorable pharmacokinetic characteristics. The oral bioavailability of irinotecan was however very variable and low as found by Berlin et al. [15] and Radomski et al. [8].
Irinotecan is used as first-line therapy in patients with metastatic carcinoma of the colon or rectum in combination with 5-fluorouracil in a treatment regimen abbreviated “FOLFIRI”. The most significant adverse effects and dose-limiting factor of Irinotecan is severe diarrhea and extreme suppression of the immune system. Irinotecan is further used in combination with capecitabine (Xeloda®) being an orally active 5-FU analogue. This analogue in combination with irinotecan was well tolerated and more convenient than irinotecan and 5-FU intravenous combinations in patients with previously untreated advanced colorectal cancer in a phase I/II clinical trial, see Rea D W et al. A solid oral dosage form of irinotecan offers the possibility for an all tablet based dose regimen “CAPIRI” of the “FOLFIRI” treatment due to the presence of capecitabine as an oral tablet formulation of 5-FU.